Tutorial: Variability in human responses to drugs Flashcards
How can absolute differences in an administered drug dose occur?
Absolute difference= the actual dose given is different due to
- a) error in prescription or dispensing
b) patient non-compliance
c) drug formulation
Explain how envoronemntal exposure to drugs or chemicals can alter relative drug dosage?
E.g. they can
- enzyme induction (increase rate of metabolism)
- enzyme inhibition (decrease rate of metabolism)
Eventually also compete with drug target, alter the amount of plasma protein levels etc, etc.
Explain the impact of food on drug responses
- drugs may interact chemically with components of food; this may alter their absorption
- e.g. foods delay gastric emptying and alter gastric pH
Explain the effect of fluids on drug response
- most drugs are better absorbed if taken with water eg may dissolve better
- fluids may stimulate gastric emptying.
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- fluids may stimulate gastric emptying.
How and why do small children/newborns have a different repsonse to drugs?
Normally: Less metabolised/ higher action due to
- more body water than adults
- poorer renal function, with immature tubular secretion
- an immature blood brain barrier
- lower capacity for drug metabolism.
Explain the things that might alter drug absorbtion in the elderly
- decreased absorptive surface of small intestine
- altered gastric and gut motility
- increased rate of gastric emptying
–> Normally: decreased absorbtion
Explain the how drug distribution differs with increased age
reduced lean body mass and body water, relative increase in fat leading to
- lipid soluble drugs have increased Vd (=volume of distribution) and decreased blood levels
- water soluble drugs have decreased Volume of distribution and increased blood levels
- reduced plasma albumin, so fewer plasma protein binding sites
Which factors influence drug metabolism in the elderly?
Is normally slower due to:
- splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
- liver size and hepatocyte number decrease
- hepatic enzyme activity and induction capacity decrease
Explain the factors that influence drug dexcretion in the elderly
Normally slower/reduced due to:
- reduced renal mass
- reduced renal perfusion
- reduced glomerular filtration rate
- reduced tubular excretion
How does nutritional status lead to variability in drug response?
- unbalanced diets may lead to deficiency states and enzyme abnormalities
- starvation – decreased plasma protein binding and metabolism
- obesity – increased lipid fraction
How can congestive heart failure lead to altered drug responses?
iii) Congestive heart failure (especially in the elderly) may lead to
- reduced splanchnic blood flow
- intestinal mucosal oedema
- reduced hepatic clearance
How can Kidney failure lead to variation in drug response?
- decreased drug excretion leading to toxicity
- water overload leading to changes in drug concentrations in different body fluid compartments
How does liver disease lead to variability in response to drugs?
It might cause:
- reduced metabolism
- reduced first pass metabolism (hence increased bioavailability)
- decreased biliary secretion and hence decreased removal
- decreased albumin synthesis and hence reduced plasma protein binding
What is pharmagocenetics?
The study of genetically determined inter-individual differences in therapeutic response to drugs ans suspectibility to adverse effects
- resticted to a single or few genes of interest
- mendelian segregation
What is pharmacogenomics?
Use of genome based techniques in drug development
- not resticted to one of few genes
- use of high thoughput technologies
How can a trait or a phenotype be regulated in the genome?
- monogenic
- polygenic
- polymorphic (frequent occuring momogenic variants of a grequency of >1% of the population)
How are phenotypes in the population distributed?
- Mutimodal (bi or trimodal) distribution
- determined by a single gene with polymorphic variants
- Unomodal distribution
- indicated polygenic or multifactural
- or monogenic inheritance without polymorphsm
Name an example of which phonetypes could be seen in a bi or tri-modal distribution of the phenotype drug metabolism
- Enhanced/extensive metaboliser
- low plasma concentration, ususally heterozygote or homozygote dominant
- intermediate metaboliser
- poor metaboliser/non-metabolser
- high plasma concentration, long time
- homozygote recesicce
Why is do people react differently to treatment of tuberculosis with isoniazid?
Because there are different polymorphisims for the ability to undertake n-acetylation reactings
- might lead to overdosing in some people with slow metabolism
What does the Hardy-Weinberg law predict?
Both allele and genotype frequencies ina population remain constant (are in equilibrium) from generation unless specific disturbing factors are introduced
- Phenotyßpe: observed fast and slow metaboliser
- Genotype: Genetic makeu (FF; SS; FS; SF)
- Allele= individual copy (F or S)
Explain the calculation of the Hardy-Weinberg-Law
(p+q)2 = p2 + 2pq + q2 = 1
- =1 because it is bimodal –> have to add up to 100%
- 0.2601+0.4998+0.2401= 1
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